Parkinson's disease is one of the representative neurodegenerative diseases in the elderly caused by degeneration or loss of Dopamine neurons and is designated as a specified disease (intractable disease). The prevalence of Parkinson's disease is considered to be 100 to 300 people per 100,000 of the population, and the clinical symptoms can be roughly divided into motor symptoms and non-motor symptoms. As the motor symptoms, extrapyramidal symptoms such as tremor, akinesia, rigidity, and postural instability are observed, and among these, three symptoms: tremor, akinesia, and rigidity are known as three main characteristic features of Parkinson's disease.
On the other hand, as the non-motor symptoms, for example, gastrointestinal symptoms such as constipation and drooling, autonomic nervous symptoms such as orthostatic hypotension, postprandial hypotension, hyperhidrosis, oily skin, urination disorders, and erectile dysfunction, or psychiatric symptoms such as apathy, anhedonia, depressive symptoms, anxiety, and visual hallucination are developed. In addition, it is often the case that patients with Parkinson's disease also develop a cognitive impairment such as dementia.
Further, it is known that there are some cases where symptoms similar to those of Parkinson's disease are caused by diseases such as cerebrovascular disorders, brain tumors, and encephalitides, or side effects of drugs, intoxication, etc. other than Parkinson's disease. Those secondarily causing symptoms similar to those of Parkinson's disease are collectively called symptomatic parkinsonism, and symptomatic parkinsonism and primary parkinsonism such as Parkinson's disease are collectively called Parkinson's syndrome in some cases.
As a representative means for treating Parkinson's disease and/or Parkinson's syndrome, dopamine replacement therapy has been carried out. Levodopa (L-DOPA or L-3,4-dihydroxyphenylalanine), which is one of the drugs to be used in the dopamine replacement therapy, is a drug developed in the late 1960's, but has been still used at present as a first-choice drug in the treatment of Parkinson's disease.
However, levodopa has pharmacokinetic problems and also is one of the drugs whose blood concentration is difficult to be controlled at around an effective blood concentration. When levodopa is orally administered, levodopa is rapidly absorbed by an amino acid transporter present in the upper small intestine. The blood concentration of levodopa reaches a maximum value at about 30 minutes to 2 hours after oral administration, and the half-life of levodopa in the blood is about 1 hour, which is very short. Further, the absorption of levodopa is susceptible to the gastric residence time, the acidity of gastric acid, etc., and therefore is not stable.
Then, 95% or more of the absorbed levodopa is metabolized by an aromatic L-amino acid decarboxylase (AADC) in organs other than the central nervous system (particularly in liver) and rapidly converted into dopamine. Since dopamine cannot pass through the blood-brain barrier, dopamine produced in organs other than the central nervous system does not enter the brain. Therefore, it is considered that the percentage of levodopa which is distributed in the central nervous system and can exhibit its efficacy with respect to the absorbed levodopa is less than 1%.
As described above, since levodopa has pharmacokinetic problems that the absorption of levodopa is inconsistent, the blood retention time of levodopa is short, and the percentage of levodopa entered the central nervous system (brain uptake index) is low, levodopa is required to be taken 3 times or more per day, and some patients require to take levodopa as many as 12 times per day.
Moreover, levodopa also has a problem that the drug efficacy is gradually lost when several years have passed from the start of the treatment. This is because as the disease progresses, an ability to store dopamine in the brain decreases so that the range (therapeutic range) of blood concentration of levodopa, in which an appropriate therapeutic effect is obtained, is reduced. Due to this undesired property, even if a therapeutic effect is obtained by taking levodopa three times per day in a patient at present, after several years, the patient will have to take levodopa more than three times per day.
Since the problem of levodopa that “large number of doses are required” has been recognized from a long time ago, in order to overcome the problem and obtain even a slightly higher therapeutic effect on Parkinson's disease and/or Parkinson's syndrome, a method for administering levodopa at a high dose, or a method for inhibiting an aromatic L-amino acid decarboxylase in peripheral tissues was contemplated in the past. As for the inhibition of an aromatic L-amino acid decarboxylase in peripheral tissues, an inhibitor of the enzyme (DCI: a dopa decarboxylase inhibitor) has been developed, and a preparation obtained by adding a DCI to levodopa (a levodopa/DCI combination preparation) is clinically used at present. With respect to the levodopa/DCI combination preparation, the brain uptake index of levodopa has been improved as compared with the case where only levodopa is taken, and the dose of levodopa is decreased to about one-fifth. However, the half-life of levodopa in the blood does not change and is still about 1 hour or so even if a DCI is added, and therefore, from the viewpoint of maintaining the blood concentration of levodopa, there is nothing developed.
On the other hand, as for the administration of levodopa at a high dose, from the viewpoint of side effects, the implementation is not practical. The effective range of blood concentration of levodopa is narrow and also is close to the toxic range. In a case where a treatment was attempted by actually administering levodopa continuously at a dose close to the upper limit of the effective blood concentration or slightly exceeding the limit, side effects such as gastric symptoms, orthostatic hypotension, and palpitation were caused in the initial stage of the treatment, and after 2 to 3 months from the start of the treatment, dyskinesia and serious central nervous system side effects such as psychiatric symptoms were developed. Among the patients who require levodopa, there are not a few patients who cannot take levodopa at a sufficient dose due to such side effects.
The problem that levodopa requires “large number of doses” is not improved even by using levodopa and an inhibitor of levodopa metabolism in combination or by changing the administration route of levodopa itself. Further, side effects such as dyskinesia developed by frequent exposure to levodopa at a concentration exceeding the effective blood concentration are also problems which have been desired to be solved for patients who require levodopa.
In light of these circumstances, many prodrugs of levodopa itself have been reported so far for solving the problems attributed to the blood kinetics of levodopa such as “large number of doses” and “the incidence of side effects due to frequent dosing”.
Examples of the prodrugs of levodopa include the following compounds:
a conjugate of levodopa and GABA represented by the general formula (A) described in WO 2009/101616:
(wherein R1A to R3A each independently represent a hydrogen atom, a 4-aminobutyryl, or butyryl group; and R4A represents a hydrogen atom, an alkyl, butyryloxyalkyl, or 4-aminobutyryloxyalkyl group) (incidentally, the definitions of the respective groups are excerpts) (see PTL 1);
3,3-dimethyl-butyric acid 4-((S)-2-amino-2-methoxycarbonyl-ethyl)-2-(3,3-dimethyl-butyryloxy)phenyl ester represented by the formula (B) described in WO 2009/022098:
(see PTL 2);
a compound represented by the general formula (C) described in WO 2008/079387:
(wherein R1C represents C1-8 alkyl, substituted C1-8 alkyl, C1-8 alkoxy, or the like; R2C and R1C each independently represent C1-8 alkyl, substituted C1-8 alkyl, C1-8 alkoxy, or the like; and R1C and R5C each independently represent a hydrogen atom, C1-8 alkyl, substituted C1-8 alkyl, or the like) (incidentally, the definitions of the respective groups are excerpts) (see PTL 3);
a compound represented by the general formula (D) described in WO 2007/104959:
(wherein R1D and R2D each independently represent —C(═O)R5D or —C(═O)OR5D, or at least one of R1D and R2D represents a hydrogen atom and the other represents —C(═O)R5D or —C(═O)OR5D; R3D and R1D each independently represent a hydrogen atom, C1-C6 alkyl which may be substituted, C3-C6 cycloalkyl, or the like; R5D represents a hydrogen atom, C1-6 alkyl which may be substituted, or —CH2QD; and QD represents a 3- to 6-membered monocyclic carbocyclic ring or heterocyclic ring) (incidentally, the definitions of the respective groups are excerpts) (see PTL 4);
a compound represented by the general formula (E) described in WO 2007/109882:
(wherein XE represents NR7E (wherein R7E represents a hydrogen atom, an acyl group, or the like); R1E represents a hydrogen atom, NH2, C1-10 alkyl, or the like; R2E represents a hydrogen atom, C1-10 alkyl, or the like; R′2E represents a hydrogen atom, C1-10 alkyl, or the like; R3E represents a hydrogen atom, ═O, SR8E (wherein R8E represents a hydrogen atom, C1-10 alkyl, or the like), or the like; R1F and R5E each independently represent OH, NH2, or SH; and R6E represents a hydrogen atom, F, Cl, Br, I, or the like) (incidentally, the definitions of the respective groups are excerpts) (see PTL 5);
a compound represented by the general formula (F) described in WO 2006/119758:
(wherein R1F and R2F each independently represent —H, —CO—H, —CO—CH3, or the like; R3F represents —CH2CH2—R5F, —H, —CH3, —C2H5, or the like; R1F and R5F each independently represent —CO—R6F, —CO—R7F, —H, or the like; and R6F and R7F each independently represent a linear alkyl chain having 2 to 25 carbon atoms, a branched alkyl chain having 2 to 25 carbon atoms, or the like) (incidentally, the definitions of the respective groups are excerpts) (see PTL 6);
a compound represented by the general formula (G) described in WO 2005/121070:
(wherein R1G and R2G each independently represent a hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, or the like; R3G and R4G each independently represent a hydrogen atom, —C(O)OR7G, C(O)R7G, or the like; R5G is selected from alkyl, substituted alkyl, aryl, substituted aryl, and the like; R7G is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and the like; and nG represents an integer of 1 to 6) (incidentally, the definitions of the respective groups are excerpts) (see PTL 7);
a compound represented by the general formula (H) described in WO 2005/121069:
(wherein QH is selected from —XH—CO— and —CO—XH—; XH is selected from —O— and —NR6H; R6H is selected from a hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, and the like; nH represents an integer of 2 to 4; R1H and R2H are each independently selected from a hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, and the like; R3H and R4H are each independently selected from a hydrogen atom, —C(O)OR7H, C(O)R7H, and the like; R5H is selected from a hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, and the like; and R7H is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and the like) (incidentally, the definitions of the respective groups are excerpts) (see PTL 8);
a compound represented by the general formula (J) described in European Patent Application Publication No. 728469:
(wherein X1J represents a hydrogen atom, hydroxyl, methoxy, ethoxy, acetyloxy, or the like; X2J represents hydroxy, methoxy, ethoxy, acetyloxy, or the like; mJ+nJ is 5 or less; R1J represents carbonyl, alkoxycarbonyl, benzyloxycarbonyl, or the like; R2J represents a hydrogen atom, alkyl, alkylcarbonyl, alkyloxycarbonyl, benzyloxycarbonyl, or the like; and R3J represents a hydrogen atom, an alkyl group, or the like) (incidentally, the definitions of the respective groups are excerpts) (see PTL 9);
a compound represented by the general formula (K) described in Japanese Patent Application Publication No. S49-061135:
(wherein nK represents an integer of 0 to 2) (see PTL 10);
a compound represented by the general formula (L) described in German Patent Application Publication No. 2153800:
(wherein R1L represents C1-7 alkoxy, C3-8 alkenylalkoxy, or phenyl C1-7 alkoxy; R2L represents a hydrogen atom; R3L represents a hydrogen atom, a substituent containing 1 to 18 carbon atoms, or the like; and R4L represents a substituent containing 1 to 18 carbon atoms or the like) (incidentally, the definitions of the respective groups are excerpts) (see PTL 11);
a compound represented by the general formula (M) described in U.S. Pat. No. 4,065,566:
(wherein RM represents a hydrogen atom, an acyl group, or
R1M represents a hydroxyl group or a —OMM group; MM represents an alkali metal or an ammonium ion; and R2M represents
(incidentally, the definitions of the respective groups are excerpts) (see PTL 12);
a compound represented by the general formula (P) described in Japanese Patent Application Publication No. S47-031949:
(wherein R1P represents a hydrogen atom or an ester residue; and R2PCO represents an organic acyl group) (incidentally, the definitions of the respective groups are excerpts) (see PTL 13);
a compound represented by the general formula (Q) described in Japanese Patent Application Publication No. S50-029527:
(wherein nQ represents 0 to 2; and RQ represents CH3 or C2H5) (see PTL 14);
a compound represented by the general formula (S) described in Japanese Patent Application Publication No. S48-072150:
(wherein R1S represents a hydrogen atom, a lower alkyl group or a carboxyl-protecting group; and R2S represents an amino-protecting group) (see PTL 15);
a compound represented by the general formula (T) described in Japanese Patent Application Publication No. S47-031950:
(wherein R1T represents a hydrogen atom or an ester residue; and R2TCO represents an organic acyl group) (incidentally, the definitions of the respective groups are excerpts) (see PTL 16);
a compound represented by the general formula (U) described in U.S. Pat. No. 3,998,799:
(wherein RU represents a hydrogen atom, an acyl group, or the like; R1U represents a hydroxyl group or a —OMU group; MU is selected from the group consisting of an alkali metal and an ammonium ion; R2U represents —COR3U; and R3U represents an N,N—(C1-C2)-dialkylamino acid, a C4-C6-cycloalkylamino acid, or the like) (incidentally, the definitions of the respective groups are excerpts) (see PTL 17); and
a compound represented by the formula (V) described in Neuropsychobiology, 1988, Vol. 19, No. 4, PP. 180-185:
(see NPL 1).
However, (2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)propanoic acid, a salt thereof, or a solvate thereof, and the use thereof disclosed in the present invention are not described in any of these prior arts, and also are not derived from a combination of any of these prior arts.